Decarboxylation treatment



United States Patent 9 DECARBOXYLATION TREATMENT Application February 9,19515 Serial No. 564,585}

1 Claim. (Cl. 260-2955) No Drawing.

This invention relates to a process for the preparation of esters ofpyridine carboxylic acids, and relates more particularly to a novelprocess for the production of pyridine carboxylic acid esters frompyridine dicarboxylic acids.

An object of this invention is the provision of an improved process fordecarboxylating isocinchorneronic acid whereby nicotinic acid isobtained.

Another object of this invention is to provide an improved process forthe production of nicotinic acid esters from isocinchomeronic acid inwhich the decarboxylation of isocinchomeronic acid is carried out in areaction medium adapted to effect the esterification of the nicotinicacid formed.

Other objects of this invention will appear from the following detaileddescription.

Niacin and niacinamide are widely recognized and em ployed asnutritional factors in the prevention and treatment of pellagra. Thesecompounds have been made available synthetically by various chemicalprocesses. One of the more practical methods for synthesizing niacin,also known as nicotinic acid, involves the oxidation of aldehydecollidine, or 2-methyl-5-ethyl pyridine, with nitric acid. During thisoxidation process the corre' sponding 2,5-pyridine dicarboxylic acid isformed. Under suitable heating conditions, especially at highertemperatures, the dicarboxylic acid, also known as isocinchorneronicacid, undergoes decarboxylation during the course of the oxidation toform niacin. In the process described in Swiss Patent No. 234,588 niacinis obtained directly with the decarboxylation taking place in the nitricacid oxidation medium itself without any separation of theisocinchomeronic acid formed. The optimum reaction conditions foroxidation and decarboxylation are not analogous. The oxidation proceedsmost favorably at temperatures of from about 175 to about 195 C. whiledecarboxylation, although it will take place at temperatures within thisrange, is more easily and more rapidly efiectecl at higher temperatures.A balance of the advantages of a separate decarboxylation over thecombined oxidation and decarboxylation favors separate decarboxylation,especially Where nitric acid is employed, due not only to the excessivecorrosion experienced with nitric acid at the higher temperatures wheredecarboxylation is most rapid, but also to possible decomposition underthe drastic conditions inherent whenever nitric acid is used at hightemperatures.

The separate decarboxylation of isocinchomeronic acid has been carriedout successfully in various inert media including acetic acid, water,sulfuric acid and mineral oil, and the reaction conditions forsubstantially complete decarboxylation to niacin are, essentially, asuitable combination of time and temperature.

In producing certain niacin derivatives such as niacinamide, forexample, an important intermediate step com- "ice prises theesterification of the niacin to form a lower alkyl ester, such as themethyl, ethyl, propyl, isopropyl or butyl ester. Niacinamide is formedby an ammonolysis reaction which comprises heating the niacin ester withammonia. Thus, in the usual process for producing niacinarnide, theconversion of isocinchomeronic acid to niacin and the esterification ofthe niacin comprise two separate and distinct steps in the process.

We have now found, however, that isocinchomeronic acid may bedecarboxylated and the niacin formed simultaneously esterified if thedecarboxylation is carried out in a medium comprising a lower aliphaticalcohol, said reaction medium preferably containing up to 25% by weightof Water on the weight of the lower aliphatic alcohol. The presence ofwater in the reaction mixture has been found to repress esterificationof the a-carboxyl group on the dicarboxylic acid and thus ensuresmaximum decarboxylation.

ecarboxylation and esteriiication are effected by heating the reactionmixture of isocinchomeronic acid, lower aliphatic alcohol and water to atemperature of 180 to 250 C. and maintaining the reaction mixture atthis temperature for from 2 to 5 hours.

In order further to illustrate our invention but without being limitedthereto, the following examples are given:

Example I parts by weight of isocinchomeronic acid are added to 405parts by weight of n-butanol containing 5% parts by weight of water andthe mixture heated under autogenous pressure at 260 C. for 3%. hours.The reaction product is then cooled. Decarboxylation to niacin is foundto be 98% complete with 70% of the niacin produced being esterified toform n-butyl nicotinate. About 1.5% of the isocinchorneronic acid isesterified to form di-n-butyl-isocinchomeronate.

Example II 109 parts by weight of isocinchomeronic acid are added to asolution of 75 parts by weight of Water in 405 parts by weight ofn-butanol and the mixture heated at 200 C. for 3 /2 hours Whilemaintaining the pressure at 300 pounds per square inch gauge. Thereaction mixture formed is cooled and, by assay, the degree ofdecarboxylation to niacin is found to be 99.5% complete of which 34% isesterified to form n-butyl nicotinate. About 0.5% of theisocinchomeronic acid is unreacted.

it is understood that the foregoing detailed description is given merelyby Way of illustration and that many variations may be made thereinwithout departing from the spirit of our invention.

Having described our invention, what we desire to secure by LettersPatent is:

Process for the production of n-butyl nicotinate, which comprisesheating isocinchomeronic acid under autogenous pressure to adecarboxylating temperature of 180 to 250 C. in a reaction mediumcomprising n-butanol and containing from 12 to 25 by weight of water onthe weight of the n-butanol.

References Cited in the file of this patent UNITED STATES PATENTS2,389,065 Lee et al Nov. 13, 1945 2,702,802 Aries Feb. 22, 19552,721,202 Wirz Oct. 18, 1955 FOREIGN PATENTS 724,256 Great Britain Feb.16, 1955

